EP1390371B1 - Oxazolopyrimidines et furopyrimidines et utilisation dans des agents pharmaceutiques contre les tumeurs - Google Patents

Oxazolopyrimidines et furopyrimidines et utilisation dans des agents pharmaceutiques contre les tumeurs Download PDF

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EP1390371B1
EP1390371B1 EP02740590A EP02740590A EP1390371B1 EP 1390371 B1 EP1390371 B1 EP 1390371B1 EP 02740590 A EP02740590 A EP 02740590A EP 02740590 A EP02740590 A EP 02740590A EP 1390371 B1 EP1390371 B1 EP 1390371B1
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alkyl
signifies
formula
aryl
compound
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EP1390371A1 (fr
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Guido Bold
Paul William Manley
Andreas Martin-Kohler
Urs Sequin
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Novartis Pharma GmbH
Novartis AG
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Novartis Pharma GmbH
Novartis AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to oxazolo- and/or furopyrimidine derivatives, intermediates and processes for their production, pharmaceutical formulations comprising these compounds, and their usage as medicaments or in the preparation of medicaments.
  • Tumour diseases are one of the most important causes of death in industrialised countries. Very great efforts have been made to provide effective compositions and methods of treating tumours. Owing, in particular, to the large number and wide variation of possible tumour diseases, there is a constant need for new pharmacologically active compounds and compositions, which, because of their active substances, are either suitable for treating as many tumour diseases as possible or alternatively are suitable for treating specific tumour diseases. In addition, there are a number of further proliferative diseases or diseases based on missing or defective physiological regulation.
  • US 6 096 749 A discloses pyrrolo-pyrimidines as inhibitors of EGF.
  • the invention relates to a compound of formula I, wherein X either signifies nitrogen, or a carbon atom bearing a radical A; A signifies hydrogen or -COOW, wherein W is hydrogen or alkyl, aryl, heterocyclyl or cycloalkyl, whereby each of these radicals is unsubstituted or substituted; Y is NR', S or 0, whereby R' signifies hydrogen or alkyl; R signifies aryl, heterocyclyl, cycloalkyl, aryl-alkyl, heterocyclyi-alkyl or cydoalkyl-alkyl, whereby each of these radicals is unsubstituted or substituted; or it is COOR', COR' or CONR'R", wherein R' and R", independently of one another, are hydrogen or alkyl, aryl, heterocyclyl, cycloalkyl, aryl-alkyl, heterocyclyl-alkyl or cycloalkyl-alkyl
  • the prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either unbranched or branched with single or multiple branching.
  • Asymmetric carbon atoms that are optionally present in the substituents may exist in the (R), (S) or (R,S) configuration, preferably in the (R) or (S) configuration.
  • the present compounds may thus exist as mixtures of isomers or as pure isomers, preferably as pure diastereoisomers or enantiomers.
  • Alkyl is preferably an alkyl radical with 1 to 20, especially 1 to 10, carbon atoms, preferably lower alkyl, especially methyl.
  • Alkyl is unbranched or has single or multiple branching.
  • Alkyl is unsubstituted or is substituted by one or more, preferably up to three, especially 1 or 2, substituents, selected, independently of one another, from those named below as substituents for aryl.
  • Lower alkyl is unbranched or has single or multiple branching, and is in particular methyl or ethyl, or also n-propyl, isopropyl, n-butyl, sec.-butyl or tert.-butyl.
  • Aryl is preferably an aromatic radical with 6 to 18, preferably 6 to 14 carbon atoms, especially phenyl, naphthyl, fluorenyl or phenanthrenyl, whereby aryl, especially the said radicals, may be unsubstituted or substituted by one or more Substituents, preferably up to three, primarily one or two substituents, especially selected from amino; lower alkylamino; N,N-di-lower-alkylamino; amino lower alkyl; lower alkylamino lower alkyl; N,N-di-lower alkylamino lower alkyl; lower alkanoylamino, especially acetylamino; halogen, especially fluorine, chlorine or bromine; lower alkyl, especially methyl or also ethyl or propyl; lower alkenyl; phenyl; naphthyl; halogen lower alkyl, especially trifluoromethyl; hydroxy; lower alkoxy, especially me
  • aryl which is substituted by one or more substituents is, in particular, lower alkylpiperazinylcarbonylphenyl, morpholinylcarbanylphenyl, N,N-di-lower alkylcarbamoylphenyl, lower alkylpiperazinyl lower alkylphenyl, morpholinyl lower alkylphenyl or N,N-di-lower alkylamino lower alkylphenyl.
  • Halogen is especially fluorine, chlorine, bromine, or iodine, in particular fluorine or chlorine.
  • Halogen lower alkyl is methyl or ethyl that is substituted in particular by halogen, such as fluorine or chlorine, especially methyl fluoride or also methyl chloride.
  • Hydroxy lower alkyl is in particular lower alkyl which is terminally substituted by hydroxy, preferably hydroxymethyl.
  • Heterocyclyl is preferably a wholly saturated, partly saturated or unsaturated radical and is preferably monocyclic, or also bi- or tricyclic; it preferably has 1 to 20, especially 1 to 14 ring atoms, whereby one or more, especially one to four, primarily one or two of the ring atoms present at least in the ring which is bonded to the remaining radical of the compound of formula I, and/or in further rings, where present, are hetero atoms selected especially from the group comprising nitrogen, oxygen and sulfur, whereby heteroaryl is unsubstituted or substituted by one or more substituents selected, independently of one another, from those named as substituents for aryl; and it is especially selected from the group comprising pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, qui
  • Cycloalkyl is preferably C 3 -C 12 , especially C 3 -C 8 -cycloalkyl, and is in particular cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and is unsubstituted or substituted by one or more, especially one to three, preferably one or two of the substituents named, independently of one another, as substituents for aryl.
  • Arylalkyl is preferably aryl lower alkyl, for example arylmethyl, whereby aryl is preferably defined as above and is unsubstituted or is substituted as described above.
  • Heterocyclylalkyl is preferably heterocyclyl lower alkyl, for example heterocyclylmethyl, whereby heterocyclyl is preferably defined as above and is unsubstituted or is substituted as described above.
  • Cycloalkylalkyl is preferably cycloalkyl lower alkyl, for example cycloalkylmethyl: whereby cycloalkyl is preferably defined as above and is unsubstituted or is substituted as described above.
  • a carbon atom which bears a radical A has the formula C(A).
  • Salts are primarily the pharmaceutically acceptable salts of compounds of formula I. Salts may be formed provided that salt-forming groups are present in a compound of formula l. Salts of compounds of formula I are in particular acid addition salts (if a basic group is present in the relevant compound of formula I, such as amino or imino), or salts with cations or bases (if an acidic group, such as carboxy, is present in the relevant compound of formula I); where several salt-forming groups are present, interrial salts or mixed salts may also be present.
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, hydrohalic acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • salts with suitable cation salts or bases may be present, such as non-toxic metal salts of groups Ia, Ib, IIa or IIb of the periodic table of elements, especially suitable alkali metal salts, such as lithium, sodium or potassium, or alkaline earth metal salts, such as magnesium or calcium salts, or zinc or ammonium salts, or also salts with organic amines, such as unsubstituted or substituted mono-, di- or trialkytamines, especially mono-, di- or tri-lower alkylamines, or with quatemary ammonium compounds, for example with N-Methyl-N-ethylamine, diethylamine, triethylamine, mono-, bis- or tris(2-hydroxy lower alkyl)amines, such as mono-, bis- or tris(2-hydroyethyl)amine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)
  • the compounds of formula I have valuable pharmacological properties. In particular they exhibit specific inhibitory activities that are of high pharmacological interest. They are preferably active as tyrosine kinase inhibitors and/or also as inhibitors of serine/threonine protein kinases. For example, they exhibit very good inhibitory action against the tyrosine activity of the receptor for epidermal growth factor (EGF) and the receptor of the vascular endothelial growth factor (VEGF). Furthermore, they show efficacy against a series of other tyrosine protein kinases, such as c-erbB2 kinase.
  • EGF epidermal growth factor
  • VEGF vascular endothelial growth factor
  • EGF-R-TPK epidermal growth factor
  • VEGF-R-TPK vascular endothelial growth factor VEGF
  • compounds of formula I inhibit, to differing extents, other tyrosine protein kinases that are involved in signal transmission mediated by trophic factors, for example abl kinase, especially v-abl kinase, kinases from the family of src kinases, especially c-src kinase, Ick, fyn; other kinases of the er EGF family, for example c-erbB2-kinase (HER-2), c-erbB3 kinase, c-erbB4 kinase; members of the family of PDGF receptor tyrosine protein kinases, for example PDGF receptor kinase, CSF-1 receptor kinase, Kit receptor kinase and FGF receptor kinase; the receptor kinase
  • EGF-R-TPK EGF receptor-specific tyrosine protein kinase
  • EGF-R ICD the recombinant intracellular domain of the EGF-receptor
  • the compounds of formula I inhibit the enzyme activity by 50 % (IC 50 ), for example in a concentration of from 0.001 to 100 ⁇ M, especially from 0.001 to 20 ⁇ M.
  • c-erbB2 tyrosine kinase HER-2
  • EGF-R-TPK EGF-R-TPK
  • the c-erbB2 kinase can be isolated, and its activity determined, by means of protocols known per se, for example in accordance with T. Akiyama et al.; Science 232 , 1644 (1986).
  • the activity of the compounds of formula I on EGF-stimulated cellular tyrosine phosphorylation in the EGF-receptor can be determined in the human A431 epithelial carcinoma cell line by means of an ELISA (EGFR-ELISA) which is described in U. Trinks et al., J. Med. Chem. 37:7 , 1015-1027 (1994).
  • EGFR-ELISA ELISA
  • kits, Flt-1 or also KDR may be carried out using the respective tyrosine kinase, which can be used as the glutathione-S-transferase fusion protein using, for example, a baculovirus system.
  • the respective fusion proteins are purified by chromatography using a glutathione-sepharose column, and used to determine the IC 50 values of the test compounds of formula I.
  • IC 50 values in the range of 1 nM to 200 ⁇ M could be found, for example with KDR in the range of 100 nM to 100 ⁇ M.
  • the compounds of formula I likewise also exhibit an inhibition in cell growth of EGF-dependent cell lines, such as the epidermoid BALB/c mouse keratinocyte cell line (see Weissmann, B.A., and Aaronson, S.A., Cell 32 , 599 (1983)) or of the A431 cell line, which are recognised as useful standard sources of EGF-dependent epithelial cells (see Carpenter, G., and Zendegni, J. Anal. Biochem. 153 , 279-282 (1985)).
  • EGF-dependent cell lines such as the epidermoid BALB/c mouse keratinocyte cell line (see Weissmann, B.A., and Aaronson, S.A., Cell 32 , 599 (1983)) or of the A431 cell line, which are recognised as useful standard sources of EGF-dependent epithelial cells (see Carpenter, G., and Zendegni, J. Anal. Biochem. 153 , 279-282 (1985)).
  • the inhibitory action of the compounds of formula I is determined in short as follows: BALB/MK cells (10,000/microtitre plate well) are transferred to 96-well microtitre plates. The test compounds (dissolved in DMSO) are added in a series of concentrations (dilution series), so that the final concentration of DMSO is no greater than 1% (v/v). After the addition, the plates are incubated for three days, during which time the control cultures without test substance may undergo at least three cell division cycles. The growth of MK cells is measured by methylene blue dyeing: After incubation, the cells are fixed with glutaraldehyde, washed with water and stained with 0.05% methylene blue.
  • the IC 50 value in those experiments is given as that concentration of the test compound in question that results in a cell count that is 50 % lower than that obtained using the control without inhibitor.
  • the compounds of formula I may effect inhibition of the growth of tumour cells also in vivo, as shown, for example, by the test described below: the test is based on inhibition of the growth of the human epidermoid carcinoma A431 (ATCC No. CRL 1555; American Type Culture Collection, Rockville, Maryland, USA; see Santon, J.B., et al., Cancer Research 46 , 4701-4705 (1986) and Ozawa, S., et al ., Int. J. Cancer 40 , 706-710 (1987)), which is transplanted into female BALB/c nude mice (Bomhoitgard, Denmark). That carcinoma exhibits a growth that correlates with the extent of the expression of the EGF-receptor.
  • tumours having a volume of approximately 1 cm 3 cultured in vivo are surgically removed from experimental animals under sterile conditions.
  • the tumours are comminuted and suspended in 10 volumes (w/v) of phosphate-buffered saline.
  • the suspension is injected s.c. (0.2 ml/mouse in phosphate-buffered saline) into the left flank of the animals.
  • 1 x 10 6 cells from an in vitro culture in 0.2 ml of phosphate-buffered saline can be injected.
  • Treatment with test compounds of formula I is started 5 or 7 days after the transplant, when the tumours have reached a diameter of 4-5 mm.
  • tumour growth is determined by measuring the diameter of the tumours along two axes that are perpendicular to each other.
  • the tumour volumes are calculated using the known formula p x L x D 2 /6 (see Evans, B.D., et al., Brit. J. Cancer 45 , 466-8 (1982)).
  • cell line A-431 alternatively to the cell line A-431, other cell lines may also be used to demonstrate the antitumour activity of compounds of formula I in vivo, for example: .
  • the cells are washed twice with ice-coid PBS (phosphate-buffered physiological, saline) and immediately lysed in 100 ⁇ l lysis buffer per batch.
  • PBS phosphate-buffered physiological, saline
  • the lysates are then centrifuged to remove the cell nuclei, and the protein concentrations of the supematants are determined using a commercial protein assay (BIORAD).
  • BIORAD commercial protein assay
  • a sandwich ELISA is carried out to measure the KDR-receptor phosphorylation.
  • a KDR-specific monoclonal antibody for example Mab 1495.12.14; prepared by H. Towbin
  • a KDR-specific monoclonal antibody for example Mab 1495.12.14; prepared by H. Towbin
  • black ELISA plates OptiPlateTM HTRF-96 from Packard
  • the plates are then washed and the remaining free protein binding sites are saturated with 1 % bovine serum albumin in PBS.
  • the cell lysates (20 ⁇ g protein/batch) are then incubated overnight at 4°C with an antiphosphotyrosine antibody ligated with alkaline phosphatase (PY20:AP from Transduction Laboratories).
  • the known rat adjuvant arthritis model (Rat Adjuvant Arthritis Model; Pearson, Proc. Soc. Exp. Biol. 91, 95-101 (1956)) is used to demonstrate the anti-arthritic activity of a compound of formula I.
  • Male Wistar rats (5 animals per group, weight ca. 200 g, acquired from Iffa Credo, France) are individually injected i.d. (intradermally) via the tail with 0.1 ml of mineral oil containing 0.6 mg of lyophilised heat-inactivated Mycobacterium tuberculosis.
  • the rats are treated with test compound (3,10 or 30 mg/kg p.o. once daily) or with the carrier material (water) from day 15 to day 22 (therapeutic dosage scheme).
  • the effect of a compound of formula I on pain may be demonstrated in the following model for noci-reception.
  • hyperalgesia which is caused by an intraplanar yeast injection is measured by using increasing pressure on the foot until the test animal cries out or removes the paw from the pressure cushion being applied.
  • the model reacts to COX inhibitors, and diclofenac (3 mg/kg) is used as a positive control.
  • the baseline pressure which is required to induce a vocal sound or removal of the paw is determined individually (2 hours before treatment) on male Sprague-Dawley rats (weight ca. 180 g, acquired from lffa Credo, France). Then, 100 ⁇ l of a 20% yeast suspension in water is injected into the hind paws. 2 hours after this, the rats are treated by oral administration with the test compound (3, 10 or 30 mg/kg) or with diclofenac (3 mg/kg) or with the carrier material (physiological saline) p.o. (point of time: nill), and the pressure test is repeated 1 and 2 hours after administration. Using the standard apparatus (Ugo Basile, Italy), the pressure needed to induce a vocal expression or removal of the paw is measured at these points in time on animals treated with the test compound and compared with those treated with only the carrier material.
  • the compounds of formula I are suitable especially for treating inflammatory rheumatic or rheumatoid diseases, in particular their manifestation on the locomotor system, for example inflammatory rheumatoid diseases such as polyarthritis, and/or for treating pain.
  • the compounds of formula I inhibit in particular the growth of blood vessels, and are thus, for example, effective against a series of diseases associated with deregulated angiogenesis, especially diseases caused by ocular neovascularisation, such as diabetic retinopathy or age-induced macula degeneration; psoriasis, haemangioblastoma, sich as haemangioma; proliferative diseases of mesangial cells, such as chromic or acute renal diseases, for example diabetic nephropathy, malignant nephroscierosis, thrombotic microanglopathy syndrome, transplant rejection, or especially inflammatory renal diseases, such as glomerulonephritis, especially mesangioproliferative glomerulonephritis, haemolytic uremic syndrome, diabetic nephropathy or hypertensive nephrosclerosis; atheroma, arterial restenosis; autoimmune diseases, acute inflammation
  • the compounds of formula I are especially useful in the treatment of benign or malignant tumours. They are capable of effecting tumour regression and of preventing the formation of tumour metastases and the growth of micrometastases. They can be used especially in the case of epidermal hyperproliferation (psoriasis), in the treatment of neoplasias of epithelial character, e.g. mammary carcinomas, and in leukaemias.
  • the compounds of formula I may be used to treat diseases of the immune system, provided that several or preferably single tyrosine protein kinase(s) and/or (furthermore) serine/threonine protein kinase(s) is/are involved; the compounds of formula I may also be used in the treatment of disorders of the central or peripheral nervous system in which signal transmission by several or, preferably, a single tyrosine protein kinase(s) and/or (furthermore) serine/threonine protein kinase(s) is/are involved.
  • the present invention relates also to the use of the compounds of formula I in the inhibition of the mentioned protein kinases.
  • tumour cells or epithelial cells in the case of psoriasis
  • inhibition of proliferation for example of tumour cells or epithelial cells in the case of psoriasis
  • tumour cells or epithelial cells in the case of psoriasis
  • the compounds according to the invention can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents.
  • a compound of formula I can be administered for example in the case of tumour therapy in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these.
  • Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above.
  • Other possible treatments are therapy to maintain the patient's status after tumour regression, or even chemopreventive therapy, for example in patients at risk.
  • Therapeutic agents for possible combination are especially one or more antiprofiferative, cytostatic or cytotoxic compounds, for example a chemotherapeutic agent or several agents selected from the group which includes, but is not limited to, an inhibitor of polyamine biosynthesis, an inhibitor of a protein kinase, especially of a serine/threonine protein kinase, such as protein kinase C, or of a tyrosine protein kinase, such as the EGF receptor tyrosine kinase, e.g. PKI166, the VEGF receptor tyrosine kinase, e.g. PTK787, or the PDGF receptor tyrosine kinase, e.g.
  • a chemotherapeutic agent for example a chemotherapeutic agent or several agents selected from the group which includes, but is not limited to, an inhibitor of polyamine biosynthesis, an inhibitor of a protein kinase, especially of a serine/th
  • STI571 a cytokine, a negative growth regulator, such as TGF- ⁇ or IFN- ⁇ , an aromatase inhibitor, e.g. letrozole or anastrozole, an inhibitor of the interaction of an SH2 domain with a phosphorylated protein, antiestrogens, topoisomerase I inhibitors, such as irinotecan, topoisomerase II inhibitors, microtubule active agents, e.g.
  • paclitaxel paclitaxel, discodermolide or an epothilone, alkylating agents, antineoplastic antimetabolites, such as gemcitabine or capecitabine, platin compounds, such as carboplatin or cisplatin, anti-angiogenie compounds, gonadorelin agonists, anti-androgens, bisphosphonates, e.g. AREDIA® or ZOMETA®, and trastuzumab.
  • the structure of the active agents identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents international (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference.
  • X signifies either nitrogen or a carbon atom bearing a radical A;
  • A signifies hydrogen or -COOW, wherein W signifies alkyl or hydrogen;
  • Y is NR', S or O, wherein R' signifies hydrogen or alkyl;
  • R signifies alkyl, aryl, heterocyclyl, cycloalkyl, arylalkyl, heterocyclylalkyl or cycyoalkylalkyl, whereby each of these radicals is unsubstituted or substituted; or COOR', COR' or CONR'R" , wherein R' and R", independently of one another, are hydrogen or alkyl, aryl, heterocyclyl, cycloalkyl, arylalkyl, heterocyclylalkyl or cycloalkylalkyl, whereby each of these radicals is unsubstituted or substituted; and Q is aryl, aryl lower alkyl or hetero
  • a compound of formula I wherein X signifies either nitrogen or a carbon atom bearing a radical A; A signifies hydrogen or -COOW, wherein W signifies alkyl or hydrogen; Y is NR', S or O, whereby R' signifies hydrogen or alkyl; R signifies aryl; and Q is aryl, aryl lower alkyl or heterocyclyl, which are respectively unsubstituted or substituted, is very preferred; as well as a salt thereof.
  • the invention relates in particular to a compound of formula I, wherein X signifies either nitrogen (preferred) or a carbon atom bearing a radical A; A signifies hydrogen or -COOW, wherein W signifies alkyl, especially lower alkyl, or hydrogen; R signifies aryl; and Q signifies aryl; or a salt thereof.
  • X signifies either nitrogen or a carbon atom bearing a radical A;
  • A signifies hydrogen;
  • R is phenyl which is substituted by nitro or amino; and
  • Q is phenyl which is substituted by one or more radicals (especially 1 or 2 radicals), which, independently of one another, are selected from hydroxy, lower alkoxy, especially methoxy, and halogen, especially chlorine or bromine; or a salt thereof.
  • X signifies either nitrogen or a carbon atom bearing a radical A;
  • A signifies hydrogen;
  • R signifies aryl; and
  • Q signifies aryl, aryl lower alkyl or heterocyclyl; or a salt thereof;
  • aryl is phenyl, naphthyl, fluorenyl or phenanthrenyl, which are respectively unsubstituted or substituted by up to three substituents selected from amino; lower alkylamino; N,N-di-lower alkylamino; amino lower alkyl; lower alkylamino lower alkyl; N,N-di-lower alkylamino lower alkyl; lower alkanoylamino; halogen; lower alkyl; lower alkenyl; phenyl; naphthyl; halogen lower alkyl; hydroxy; lower alkoxy; lower alkenyloxy; phenyl lower alkoxy; lower alkanoyloxy;
  • X signifies either nitrogen or a carbon atom bearing a radical A;
  • A signifies hydrogen;
  • R is phenyl which is substituted by amino; especially 4-aminophenyl; and
  • Q is phenyl which is substituted by one or more radicals - especially 1 or 2 radicals -, which are selected, independently of one another, from hydroxy, lower alkoxy, especially methoxy, and halogen, especially chlorine or bromine.
  • X signifies either nitrogen or a carbon atom bearing a radical A; wherein A signifies hydrogen; R is phenyl which is substituted by nitro, amino, lower alkylpiperazinylcarbonyl, morpholinylcarbonyl, N,N-di-lower-alkylcarbamoyl, N,N-di-lower alkylamino lower alkyl, lower alkylpiperazinyl lower alkyl or morpholinyl lower alkyl; and Q is benzyl, phenylethyl; phenyl which is unsubstituted or is substituted by one or more radicals, which independently of one another, are selected from hydroxy, lower alkyl, lower alkoxy and halogen; pyridyl which is substituted by hydroxy or lower alkoxy; or indolyl which is substituted by halogen and lower alyl, as well as a salt thereof.
  • X and R have the significances given for a compound of formula I and L signifies a leaving group, e.g. chloride, are reacted with an amine, a phenol or thiole of formula III, Q-YH (III) wherein Q has the significances given for compounds of formula I and Y is NR', S or O, whereby R' signifies hydrogen or alkyl; wherein, if necessary, functional groups present in a compound of formula II and/or iii, which are not to take part in the reaction, are present in protected form, and protecting groups that are present are cleaved; and, if desired, an obtainable compound of formula I is converted into a different compound of formula I; an obtainable free compound of formula is converted into a salt; an obtainable salt of a compound of formula I is converted into another salt or the free compound of formula I; and/or obtainable isomeric mixtures of compounds of formula I are separated into the individual isomers;
  • a compound of formula II or III may be present in free form, or if the reaction of functional groups which should not participate in the reaction is to be prevented, in a form in which the functional groups that do not participate are protected.
  • the protecting groups are those that are usually used in the synthesis of peptide compounds, and also of cephalosporins and penicillins, as well as nucleic acid derivatives and sugars. These protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions.
  • the protecting groups for functional groups in starting materials whose transformation should be avoided include especially the conventional protecting groups that are normally used in the synthesis of peptide compounds, cephalosporins, penicillins or nucleic acid derivatives and sugars.
  • the protecting groups may, in addition to this protection, effect a selective, for example stereoselective, course of reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end products.
  • a leaving group in a compound of formula II is preferably halogen, especially bromine, or primarily chlorine or iodine.
  • Other leaving groups are conceivable, e.g. aryl- or alkyl-suffonyl groups, e.g. 4-toluenesulfonyl.
  • a suitable polar solvent especially in an alcohol, especially lower alkanol, such as methanol, propanol, isopropanol or in particular ethanol or n-butanol, or mixtures thereof, or in a melt without the addition of solvents, especially if one of the reactants is present in liquid form; at elevated temperature, preferably between ca. 60°C and reflux temperature of the relevant reaction mixture, for example under
  • the compound of formula III may also be present as a saft, for example as an acid addition salt with a strong acid, such as a hydrogen halide, e.g. the salt of hydrogen chloride, or the relevant acid may be added to the reaction mixture, for example in the presence of a suitable solvent, such as an ether, e.g. dioxane.
  • a strong acid such as a hydrogen halide, e.g. the salt of hydrogen chloride
  • a suitable solvent such as an ether, e.g. dioxane.
  • the reaction is preferably effected in an inert solvent, such as toluene, in the presence of a base, especially an alkali metal carbonate, such as dipotassium carbonate, in the presence of catalytic amounts of an appropriate noble metal catalyst complex, such as tetrakis-(triphenylphosphine)-palladium, at an elevated temperature, especially between 80 and 115°C.
  • an inert solvent such as toluene
  • a base especially an alkali metal carbonate, such as dipotassium carbonate
  • an appropriate noble metal catalyst complex such as tetrakis-(triphenylphosphine)-palladium
  • reaction between the compound of formula II and a thiole of formula III preferably takes place in known manner in a polar solvent, such as dimethylformamide, dimethyl sulfoxide or HMPT, if necessary in the presence of an appropriate catalyst, such as the palladium complex tetrakis-(triphenylphosphine)-palladium(O).
  • a polar solvent such as dimethylformamide, dimethyl sulfoxide or HMPT
  • functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned hereinabove under process a).
  • the protecting groups are then wholly or partly removed according to one of the methods described under process a).
  • a di-lower alkyl-imidazolidinone such as 1,3-dimethyl-2-imidazolidinone (DMEU)
  • DMEU 1,3-dimethyl-2-imidazolidinone
  • a tin(II) salt such as tin(II) chloride
  • an appropriate solvent such as an alcohol, e.g. ethanol, propanol or butanol, at preferred temperatures between 10°C and reflux temperature of the reaction mixture, preferably at temperatures between room temperature and 80°C.
  • Salts of a compound of formula I with a salt-forming group may be prepared in a manner known per se.
  • acid addition salts of compounds of formula I may be obtained e.g. by treatment with an acid or a suitable anion exchange reagent, and salts with cations e.g. by treatment with a metal salt, a base or a cation exchanger.
  • Salts can usually be converted to free compounds, e.g. in the case of acid addition salts by treating with a suitable basic agent, for example with alkali metal carbonates, -hydrogen carbonates, or -hydroxides, e.g. potassium carbonate or sodium hydroxide, or in the case of salts, with bases.
  • Stereoisomeric mixtures e.g. mixtures of diastereoisomers
  • Diastereoisomeric mixtures may be separated into their individual diastereoisomers by means of fractionated crystallisation, chromatography, solvent distribution, and similar procedures. This separation may take place either at the stage of one of the starting compounds or in a compound of formula I itself.
  • Enantiomers may be separated through the formation of diastereoisomeric salts, for example with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.
  • a compound of formula I in which R is a group phenyl-C(-O)-NR'R
  • R may be converted by known manner into a compound of formula I, in which R is a group phenyl-CH 2 NR'R", by means of a reaction with an appropriate reduction agent, e.g. diisobutyl aluminium hydride in tetrahydrofuran.
  • an appropriate reduction agent e.g. diisobutyl aluminium hydride in tetrahydrofuran.
  • All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably those that are inert to the reagents used and able to dissolve them, in the absence or presence of catalysts, condensing agents or neutralisiing agents, for example ion exchangers, typically cation exchangers, for example in the H + form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from -100°C to about 190°C, preferably from about -80°C to about 150°C, for example at -80 to 60°C, at room temperature, at - 20 to 40°C or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, if need be under pressure, and/or in an inert, for example an argon or nitrogen, atmosphere.
  • solvents or diluents preferably those that are inert to the
  • Salts may be present in all starting compounds and intermediates, if these contain salt-forming groups. Salts may also be present during the reaction of such compounds, provided that the reaction is not thereby disturbed.
  • isomeric mixtures that occur can be separated into their individual isomers, e.g. diastereoisomers or enantiomers, or into any mixtures of isomers, e.g. racemates or diastereoisomeric mixtures, typically as described under "Additional process steps”.
  • the solvents from which those can be selected which are suitable for the reaction in question include for example water, esters, typically lower alkyl-lower alkanoate, e.g diethyl acetate, ethers, typically aliphatic ethers, e.g. diethylether, or cyclic ethers, e.g. tetrahydrofuran, liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically methanol, ethanol or 1- or 2-propanol, nitriles, typically acetonitrile, halogenated hydrocarbons, typically dichloromethane, acid amides, typically dimethylformamide, bases, typically heterocyclic nitrogen bases, e.g.
  • carboxylic acids typically lower alkanecarboxylic acids, e.g. acetic acid, carboxylic acid anhydrides, typically lower alkane acid anhydrides, e.g. acetic anhydride, cyclic, linear, or branched hydrocarbons, typically cyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the description of the process.
  • solvent mixtures may also be used in working up, for example by chromatography or partitioning.
  • the invention relates also to those embodiments of the process in which one starts from a compound obtainable at any stage as an intermediate and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention under those process conditions, and further processes the said compound in situ.
  • a compound of formula I is prepared according to the processes and process steps defined in the examples.
  • the compounds of formula I are also obtainable in the form of hydrates, or their crystals may include for example the solvent used for crystallisation (present as solvates).
  • the present invention relates also to pharmaceutical preparations that contain a compound of formula I as active ingredient and that can be used especially in the treatment of the diseases mentioned at the beginning.
  • the preparations contain the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.
  • the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
  • the invention relates also to pharmaceutical preparations for use in a method for the prophylactic or especially therapeutic treatment of the human or animal body, especially against one of the above-mentioned diseases, to a process for the preparation thereof (especially in the form of compositions for the treatment of tumours) and to a method of treating the above-mentioned diseases, primarily tumour diseases, especially those mentioned above.
  • the invention relates also to processes and to the use of compounds of formula I for the preparation of pharmaceutical preparations which contain compounds of formula I as active component (active ingredient).
  • a pharmaceutical composition that is suitable for administration to a warm-blooded animal, especially a human or commercially useful mammal, suffering from a disease that is responsive to the inhibition of tyrosine or also serine/threonine protein kinase, for example psoriasis or especially a tumour disease, comprising a correspondingly effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof when salt-forming groups are present, together with at least one pharmaceutically acceptable carrier.
  • compositions contain from about 0.000001 % to 95 % of the active ingredient, whereby single-dose forms of administration preferably have from approximately 0.00001 % to 90 % and multiple-dose forms of administration preferably have from approximately 0.0001 to 0.5 % in the case of preparations for parenteral administration or 1 % to 20 % active ingredient in the case of preparations for enteral administration.
  • Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories or capsules. Further dosage forms are, for example, ointments, sprays, etc. Examples are capsules containing from about 0.0002 g to about 1.0 g active ingredient.
  • the pharmaceutical preparations of the present invention are prepared in a manner known per se , for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes.
  • solutions of the active ingredient and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilised preparations which contain the active ingredient on its own or together with a carrier, for example mannitol, can be made up before use.
  • a carrier for example mannitol
  • compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, if need be granulating a resulting mixture, and processing the mixture or granules, if desired, to form tablets or tablet cores, if need be by the inclusion of additional excipients.
  • Suitable carriers are especially fillers, such as sugars, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrants, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starches, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrants, such as the above-mentioned starches, also carboxymethyl starch,
  • Orally administrable pharmaceutical compositions also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as com starch, binders, and/or glidants, such as talc or magnesium stearate, and if need be stabilisers.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilisers and detergents may also be added.
  • Suitable rectally administrable pharmaceutical preparations are, for example, suppositories that consist of a combination of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • the formulations suitable for parenteral administration are primarily aqueous solutions [for example in physiological saline, obtainable by diluting solutions in polyethylene glycol, such as polyethylene glycol (PEG) 300 or PEG 400] of an active ingredient in water-soluble form, e.g. a water-soluble salt, or aqueous injectable suspensions containing viscosity-increasing agents, e.g. sodium carboxymethyl cellulose, sorbitol and/or dextran, and where appropriate stabilizers.
  • aqueous solutions for example in physiological saline, obtainable by diluting solutions in polyethylene glycol, such as polyethylene glycol (PEG) 300 or PEG 400
  • PEG 300 or PEG 400 polyethylene glycol
  • an active ingredient in water-soluble form e.g. a water-soluble salt
  • aqueous injectable suspensions containing viscosity-increasing agents e.g. sodium carboxymethyl cellulose, sorbitol and/or de
  • Solutions such as those used, for example, for parenteral administration can also be employed as infusion solutions.
  • the invention similarly relates to a process or a method for the treatment of one of the above-mentioned pathological conditions, especially a disease which responds to an inhibition of tyrosine- or also serine/threonine protein kinase, especially a corresponding tumour disease.
  • a compound of formula I can be administered as such or in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human, requiring such treatment, the compounds especially being used in the form of pharmaceutical compositions.
  • the dose administered is from approximately 0.1 mg to approximately 5 g, preferably from approximately 0.5 mg to approximately 2000 mg, of a compound of the present invention.
  • Administration takes place once or several time daily, for example 1 to 3 times daily, or at intervals, preferably e.g. every 1 to 4 weeks, for example weekly, every two weeks, every three weeks or every four weeks.
  • the present invention also relates in particular to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, especially a compound of formula I named as a preferred compound, or a pharmaceutically acceptable salt thereof, as such or in the form of a pharmaceutical formulation containing at least one pharmaceutically employable carrier, for the therapeutical and also prophylactic treatment of one or more of the above diseases.
  • the present invention also relates in particular to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, especially a compound of formula I named as a preferred compound, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical formulation for the therapeutic and also prophylactic treatment of one or more of the above diseases.
  • the starting materials of formulae II are known, are commercially available or may be produced analogously to known processes, whereby if necessary, protecting groups may also be introduced, used and cleaved again at appropriate times, analogously to the manner described above.
  • the starting materials of formula II may be produced by known processes, or they are known or are commercially available.
  • Such reactive carboxylic acid derivatives are known, may be produced according to or analogously to known processes, or are commercially available.
  • the reaction takes place especially in an appropriate solvent or solvent mixture, for example in a tertiary nitrogen base, such as pyridine, preferably in the absence of oxygen, for example under an inert gas such as argon, at an elevated temperature, for example of 30°C to reflux temperature of the reaction mixture, especially at reflux temperature.
  • a tertiary nitrogen base such as pyridine
  • an inert gas such as argon
  • the compound of formula X is reacted with an alkali metal salt of formula XI N ⁇ C-CH(Me)-A' (Xl) wherein Me is an alkali metal, especially sodium, and A' signifies a radical -COOW, wherein W signifies alkyl (preferably; especially lower alkyl, such as ethyl), aryl, heterocyclyl or cycloalkyl, whereby each of these radicals is unsubstituted or substituted, under conventional conditions (see e.g. Chem. Ber. 95, 307-318 (1962)), thereby producing a compound of formula XII, wherein R has the significances given for compounds of formula 1, and A' is defined as under formula Xl.
  • the compound of formula XII is subsequently transformed, in the presence of a suitable solvent or solvent mixture, for example a di-lower alkyl carboxylic acid amide, such as dimethylformamide, with formamide in the presence of formic acid, at elevated temperatures, for example in the range of 100 to 150°C, if required under pressure, into a compound of formula XIII, wherein R and A' have the significances given under formula XII.
  • a suitable solvent or solvent mixture for example a di-lower alkyl carboxylic acid amide, such as dimethylformamide
  • A' and R have the significances given under formula XII, while L signifies a leaving group, preferably halogen, especially chlorine.
  • the compound of formula IV may be produced from 4,6-dihydroxy-5-nitropyrimidine (Aldrich, Buchs, Switzerland), for example by reduction with tin(II) chloride according to M. lshidate et al., Chem. Pharm. Bull. 8 137-139 (1960).
  • ⁇ -keto esters of formula IX are likewise known, may be produced by known processes or are commercially available.
  • the starting material is prepared as follows:
  • Example 2a 7-(3"-chloroanilino)-2-(4'-nitroohenyl)oxazolo[5.4- d ]pyrimidine:
  • IR 3360 w , 3178 w , 1630 m , 1607 m , 1518 m , 1482 w , 1348 m , 1217 m , 1079 w , 1045 w , 855 w , 710 w , 516 w .
  • Example 4a 7-(4"-chioroanilino)-2-(4'-nitrophenyl)oxazolo[5,4- d ]pyrimidine:
  • Example 8 4-(4-chloro-2-fluoroanilino)-6-(4-aminophenyl)furo[2,3- d ]pyrimidine:
  • Example 8a 4-(4-chloro-2-fluoroanilino)-6-(4-nitrophenyl)furo[2,3- d ]pyrimidine:
  • the starting material is prepared as follows:
  • Example 13 4-(1 R -phenylethylamino)-6-(3-aminophenyl)furo[2,3- d ]pyrimidine
  • the starting material is prepared as follows:
  • the starting material is prepared as follows:
  • the starting material is prepared as follows:
  • the starting material is prepared as follows:
  • IR 3448 w , 3237 m , 3088 w , 1752 s , 1734 s , 1672 s , 1531 s , 1474 m , 1407 m , 1381 m , 1346 s , 1241 m , 1211 m .
  • the starting material is prepared as follows:
  • This second residue is boiled in 200 ml of methylene chloride, filtered by suction whilst warm, washed with methylene chloride and dried in a HV.
  • the residue obtained contains the product; m.p.: 212-220°C.
  • IR 3528 w , 3246 m , 3092 m , 2985 w , 1936 w , 1721 s , 1589 m , 1543 s , 1482 m , 1429 w , 1378 s , 1352 s , 1323 m , 1287 m , 1234 m , 1196 m , 1076 m , 1042 s .
  • IR 3338 m , 3180-2810 w (multiplett), 1708 s , 1676 s , 1589 w , 1560 m , 1526 s , 1406 w , 1348 s , 1220 w , 1105 w , 1081 w , 1041 w , 920 w , 899 w , 880 w , 803 w , 740 w , 676 w .
  • the starting material is prepared as follows:
  • the starting material is prepared as follows:
  • the reaction mixture is mixed with ice water, the aqueous phase separated and extracted with CH 2 Cl 2 .
  • the organic phase is washed twice with 5% citric acid solution and brine, dried (Na 2 SO 4 ), and concentrated by evaporation (50 g of an oil).
  • the residue is dissolved in 400 ml of formic acid and stirred for 2 days at RT.
  • the formic acid is evaporated under a vacuum.
  • the residue of evaporation is dissolved in EtOAc and dilute NaHCO 3 solution, the aqueous phase separated and extracted twice more with EtOAc.
  • the organic phases are washed with NaHCO 3 solution, H 2 O and brine, dried (Na 2 SO 4 ) and concentrated by evaporation.
  • Example 38 Dry-filled capsules: 5000 capsules, each comprising as active ingredient 0.25 g of one of the compounds of formula I mentioned in the preceding Examples, are prepared as follows:
  • active ingredient 1250 g talc 180 g wheat starch 120 g magnesium stearate 80 g lactose 20g
  • Preparation process The said substances are pulverised and forced through a sieve with a mesh width of 0.6 mm. 0.33 g portions of the mixture are filled into gelatin capsules using a capsule-filling machine.
  • Example 39 Soft capsules: 5000 soft gelatin capsules, each comprising as active ingredient 0.05 g of one of the compounds of formula I mentioned in the preceding Examples, are prepared as follows:
  • Preparation process The pulverised active ingredient is suspended in PEG 400 (polyethylene glycol with M r between about 380 and about 420, Fluka, Switzerland) and Tween® 80 (polyoxyethylene sorbitan monolaurate, Atlas Chem. ind., inc., USA, supplied by Fluka, Switrerland) and ground in a wet pulverizer to produce a particle size of about 1 to 3 ⁇ m. 0.43 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.
  • PEG 400 polyethylene glycol with M r between about 380 and about 420, Fluka, Switzerland
  • Tween® 80 polyoxyethylene sorbitan monolaurate, Atlas Chem. ind., inc., USA, supplied by Fluka, Switrerland

Claims (17)

  1. Composé de formule 1
    Figure imgb0035
    dans laquelle X représente soit azote, soit un atome de carbone véhiculant un radical A ;
    A représente hydrogène ou -COOW, dans lequel W est hydrogène ou alkyle, aryle, hétérocyclyle ou cycloalkyle dans lesquels chacun de ces radicaux est non substitué ou substitué ;
    Y est NR', S ou O, dans lequel R' représente hydrogène ou alkyle ;
    R représente aryle, hétérocyclyle, cycloalkyle, aryl-alkyle, hétérocyclyl-alkyle ou cycloalkyl-alkyle, dans lesquels chacun de ces radicaux est non substitué ou substitué ; ou est COOR', COR' ou CONR'R", dans lequel R' et R", indépendamment les uns des autres, sont hydrogène ou alkyle, aryle, hétérocyclyle, cycloalkyle, aryl-alkyle, hétérocyclyl-alkyle ou cycloalkyl-alkyle, dans lesquels chacun de ces radicaux est non substitué ou substitué ; et
    Q est aryle, aryl-alkyle, hétérocyclyle, hétérocyclyl-alkyle, cycloalkyle ou cycloalkyl-alkyle, qui sont respectivement non substitués ou substitués ; ou un de ses sels.
  2. Composé de formule 1 selon la revendication 1, dans lequel X représente soit azote, soit un atome de carbone véhiculant un radical A ;
    A représente hydrogène ou -COOW, dans lequel W représente alkyle ou hydrogène ;
    Y est NR', S ou O, dans lequel R' représente hydrogène ou alkyle ;
    R représente aryle, hétérocyclyle, cycloalkyle, aryl-alkyle, hétérocyclyl-alkyle ou cycloalkyl-alkyle, dans lesquels chacun de ces radicaux est non substitué ou substitué ; ou est COOR', COR' ou CONR'R", dans lequel R' et R", indépendamment les uns des autres, sont hydrogène ou alkyle, aryle, hétérocyclyle, cycloalkyle, aryl-alkyle, hétérocyclyl-alkyle ou cycloalkyl-alkyle, dans lesquels chacun de ces radicaux est non substitué ou substitué ; et
    Q est aryle, aryl-alkyle inférieur ou hétérocyclyle, qui sont respectivement non substitués ou substitués ;
    ou un de ses sels.
  3. Composé de formule I selon la revendication 1, dans lequel X représente soit azote, soit un atome de carbone véhiculant un radical A ;
    A représente hydrogène ou -COOW, dans lequel W représente alkyle ou hydrogène ;
    Y est NR', S ou O, dans lequel R' représente hydrogène ou alkyle;
    R représente aryle ; et
    Q est aryle, aryl-alkyle inférieur ou hétérocyclyle, qui sont respectivement non substitués ou substitués ;
    ou un de ses sels.
  4. Composé de formule I selon la revendication 1, dans lequel X représente soit azote, soit un atome de carbone véhiculant un radical A ;
    A représente hydrogène ou -COOW, dans lequel W représente alkyle ou hydrogène ;
    R représente aryle ; et
    Q représente aryle ou aryl-alkyle inférieur ;
    ou un de ses sels.
  5. Composé de formule I selon la revendication 1, dans lequel X représente soit azote, soit un atome de carbone véhiculant un radical. A ; A représente hydrogène ; R représente aryle ; et Q représente aryle, aryl-alkyle inférieur ou hétérocyclyle ; ou un de ses sels ;
    dans lequel aryle est phényle, naphtyle, fluorényle ou phénanthrényle, respectivement non substitués ou substitués par jusqu'à trois substituants sélectionnés à partir d'amino ; alkylamino inférieur ; N,N-di-alkylamino inférieur ; amino-alkyle inférieur ; alkylamino inférieur-alkyle inférieur ; N,N-di-alkylamino inférieur-alkyle inférieur ; alkanoylamino inférieur ; halogène ; alkyle inférieur ; alkényle inférieur ; phényle ; naphtyle ; halogène-alkyle inférieur ; hydroxy ; alcoxy inférieur-alkényloxy inférieur ; phényl-alcoxy inférieur ; alkanoyloxy inférieur ; carbamyle-alcoxy inférieur ; carboxy-alcoxy inférieur ; phényl-alcoxycarbonyle inférieur-alcoxy inférieur ; mercapto ; nitro ; carboxy ; alcoxycarbonyle inférieur ; phényl-alcoxycarbonyle inférieur ; cyano ; C8-C12-alcoxy ; carbamoyle ; alkylcarbamoyle inférieur ; N,N-di-alkylcarbamoyle inférieur ; N-mono- ou N,N-diphényl-alkylcarbamoyle inférieur ; alkanoyle inférieur ; phényloxy ; halogène-alkyloxy inférieur ; alcoxycarbonyle inférieur ; alkylpipérazinylcarbonyle inférieur ; morpholinylcarbonyle ; alkylpipérazinyle inférieur-alkyle inférieur ; morpholinyl-alkyle inférieur ; alkyle inférieur-mercapto ; halogèn-alkylmercapto inférieur ; hydroxy-alkyle inférieur ; alkanesulfonyle inférieur ; halogèn-alkanesulfonyle inférieur ; phénylsulfonyle ; dihydroxybora ; alkylpyrimidinyle inférieur ; oxazolyle ; alkyldioxolanyle inférieur ; pyrazolyle ; alkylpyrazolyle inférieur ; alkylènedioxy inférieur lié à deux atomes de carbone adjacents ; pyridyle ; pipérazinyle ; alkylpipérazinyle inférieur ; morpholinyle ; phénylamino ou phényl-alkylamino inférieur non substitué ou substitué dans le groupement phényle par halogène, alkyle inférieur, hydroxy, alkanoyloxy inférieur, alcoxy inférieur, carboxy, alcoxycarbonyle inférieur, carbamoyle, N-alkylcarbamoyle inférieur, N,N-di-alkylcarbamoyle inférieur, cyano, amino, alkanoylamino inférieur, alkylamino inférieur, N,N-di-alkylamino inférieur ou trifluorométhyle ; ou un radical de formule R3-S(O)m-, dans laquelle R3 est alkyle inférieur et m est 0, 1 ou 2.
  6. Composé de formule I selon la revendication 1, dans lequel X représente soit azote, soit un atome de carbone véhiculant un radical A ;
    A représente hydrogène ; R représente aryle ; et Q représente aryle, aryl-alkyle inférieur ou hétérocyclyle ; ou un de ses sels ;
    dans lequel aryle est phényle, naphtyle, fluorényle ou phénanthrényle, respectivement non substitué ou substitué par jusqu'à trois substituants sélectionnés à partir du groupe composé d'amino ; alkylamino inférieur ; N,N-di-alkylamino inférieur ; alkanoylamino inférieur ; halogène ; alkyle inférieur ; alkényle inférieur ; phényle ; naphtyle ; halogèn-alkyle inférieur ; hydroxy ; alcoxy inférieur ; alkényloxy inférieur ; phényl-alcoxy inférieur ; alkanoyloxy inférieur ; carbamyl-alcoxy inférieur ; carboxy-alcoxy inférieur ; phényl-alcoxycarbonyle inférieur-alcoxy inférieur ; mercapto ; nitro ; carboxy ; alcoxycarbonyle inférieur ; phényl-alcoxycarbonyle inférieur ; cyano ; C8-C12-alcoxy ; carbamoyle ; alkylcarbamoyle inférieur ; N,N-di-alkylcarbamoyle inférieur ; N-mono- ou N,N-diphénylalkylcarbamoyle inférieur ; alkanoyle inférieur ; phényloxy ; halogènalkyloxy inférieur ; alcoxycarbonyle inférieur ; alkyle inférieur-mercapto ; halogèn-alkylmercapto inférieur ; hydroxy-alkyle inférieur ; alkanesulfonyle inférieur ; halogèn-alkanesulfonyle inférieur ; phénylsulfonyle ; dihydroxybora ; alkylpyrimidinyle inférieur ; oxazolyle ; alkyldioxolanyle inférieur ; pyrazolyle ; alkylpyrazolyle inférieur ; alkylènedioxy inférieur lié à deux atomes de carbone adjacents ; pyridyle ; pipérazino ; phénylamino ou phényl-alkylamino inférieur non substitué ou substitué dans le groupement phényle par halogène, alkyle inférieur, hydroxy, alkanoyloxy inférieur, alcoxy inférieur, carboxy, alcoxycarbonyle inférieur, carbamoyle, N-alkylcarbamoyle inférieur, N,N-dialkylcarbamoyle inférieur, cyano, amino, alkanoylamino inférieur, alkylamino inférieur, N,N-di-alkylamino inférieur ou trifluorométhyle ; ou un radical de formule R3-S(O)m-, dans lequel R3 est alkyle inférieur et m est 0, 1 ou 2.
  7. Composé de formule I selon la revendication 1, dans lequel X représente soit azote, soit un atome de carbone véhiculant un radical A ; dans lequel A représente hydrogène ;
    R est phényle substitué par nitro, amino, alkylpipérazinylcarbonyle inférieur, morpholinylcarbonyle, N,N-di-alkylcarbamoyle inférieur, N,N-di-alkylamino inférieur-alkyle inférieur, alkylpipérazinyle inférieur-alkyle inférieur ou morpholinyl-alkyle inférieur ; et
    Q est benzyle, phényléthyle ; phényle non substitué ou substitué par un ou plusieurs radicaux qui, indépendamment les uns des autres, sont sélectionnés à partir d'hydroxy, alkyle inférieur, alcoxy inférieur et halogène ; pyridyle qui est substitué par hydroxy ou alcoxy inférieur ; ou indolyle substitué par halogène et alkyle inférieur ;
    ou un de ses sels.
  8. Composé de formule I selon la revendication 1, dans lequel X représente soit azote, soit un atome de carbone véhiculant un radical A ; A représente hydrogène ;
    R est phényle substitué par nitro ou amino ; et
    Q est benzyle, phényléthyle ou phényle non substitué ou substitué par un ou plusieurs radicaux qui, indépendamment les uns des autres, sont sélectionnés à partir d'hydroxy, alcoxy inférieur, tout particulièrement méthoxy, et halogène, tout particulièrement fluor, chlore ou brome, ou un de ses sels.
  9. Composé de formule I selon la revendication 1, dans lequel X représente soit azote, soit un atome de carbone véhiculant un radical A ; A représente hydrogène ; R est phényle substitué par amino, tout particulièrement 4-aminophényle ; et Q est benzyle, phényléthyle ou phényle substitué par un ou plusieurs radicaux qui, indépendamment les uns des autres, sont sélectionnés à partir d'hydroxy, alcoxy inférieur, tout particulièrement méthoxy, et halogène, tout particulièrement fluor, chlore ou brome, ou un de ses sels.
  10. Composé selon l'une des revendications 1 à 9, dans laquelle X représente azote.
  11. Composé selon l'une des revendications 1 à 9, dans laquelle X représente un groupe CH.
  12. Composé selon l'une des revendications 1 à 11, dans laquelle X est NH ou O.
  13. Composé de formule I selon la revendication 1 sélectionné à partir du groupe composé de :
    3-{2'-(4"-aminophényl)oxazolo[5,4-d]pyrimidin-7'-ylamino}phénol;
    3-{2'-(4"-nitrophényl)oxazolo[5,4-d]pyrimidin-7'-ylamino}phénol;
    dichlorhydrate de 7-(3"-chloroanilino)-2-(4'-aminophényl)oxazolo[5,4-d] pyrimidine ;
    7-(3"-chloroanilino)-2-(4'-nitrophényl)oxazolo[5,4-d]pyrimidine ;
    4-{2'-(4"-aminophényl)oxazolo[5,4-d]pyrimidin-7'-ylamino}phénol ;
    4-{2'-(4"-nitrophényl)oxazolo[5,4-d]pyrimidin-7'-ylamino}phénol ;
    7-(4"-chloroanilino)-2-(4'-aminophényl)oxazolo[5,4-d]pyrimidine ;
    7-(4''-chloroanilino)-2-(4'-nitrophényl)oxazolo[5,4-d]pyrimidine ;
    3-{2'-(3"-aminophényl)oxazolo[5,4-d]pyrimidin-7'-ylamino}phénol ;
    3-{2'-(3"-nitrophényl)oxazolo[5,4-d]pyrimidin-7'-ylamino}phénol ;
    7-(3"-chloroanilino)-2-(3'-aminophényl)oxazolo[5,4-d]pyrimidine ;
    7-(3"-chloroanilino)-2-(3'-nitrophényl)oxazolo[5,4-d]pyrimidine ;
    2-méthoxy-5-{2'-(3"-aminophényl)oxazolo[5,4-d]pyrimidin-7'-ylamino}phénol ;
    2-méthoxy-5-{2'-(3"-nitrophényl)oxazolo[5,4-d]pyrimidin-7'-ylamino} phénol ;
    4-(4-chloro-2-fluoranilino)-6-(4-aminophényl)furo[2,3-d]pyrimidine ;
    4-(4-chloro-2-fluoranilino)-6-(4-nitrophényl)furo[2,3-d]pyrimidine ;
    4-(3-chloroanilino)-6-(4-aminophényl)furo[2,3-d]pyrimidine ;
    4-(3-chloroanilino)-6-(4-nitrophényl)furo[2,3-d]pyrimidine ;
    4-(3-hydroxy-4-méthoxyanilino)-6-(4-aminophényl)furo[2,3-d] pyrimidine ;
    4-(3-hydroxy-4-méthoxyanilino)-6-(4-nitrophényl)furo[2,3-d]pyrimidine ;
    4-(3-hydroxy-4-méthylanilino)-6-(4-aminophényl)furo[2,3-d]pyrimidine ;
    4-(3-hydroxy-4-méthylanilino)-6-(4-nitrophényl)furo[2,3-d]pyrimidine ;
    4-(3-aminoanilino)-6-(4-aminophényl)furo[2,3-d]pyrimidine ;
    4-(3-aminoanilino)-6-(4-nitrophényl)furo[2,3-d]pyrimidine ;
    4-(1R-phényléthylamino)-6-(3-aminophényl)furo[2,3-d]pyrimidine ; et
    4-(1R-phényléthylamino)-6-(3-nitrophényl)furo[2,3-d]pyrimidine ;

    ou un de leurs sels.
  14. Composition pharmaceutique comprenant un composé de formule I, ou un de ses sels pharmaceutiquement acceptables, selon l'une des revendications 1 à 13 et au moins un véhicule pharmaceutiquement acceptable.
  15. Composé de formule I ou un de ses sels pharmaceutiquement acceptables, selon l'une des revendications 1 à 13 utilisable dans le cadre d'un traitement thérapeutique ou diagnostique du corps humain ou animal.
  16. Utilisation d'un composé de formule 1
    Figure imgb0036
    dans laquelle X représente soit azote, soit un atome de carbone véhiculant un radical A ;
    A représente hydrogène ou -COOW, dans laquelle W est hydrogène ou alkyle, aryle, hétérocyclyle ou cycloalkyle, dans lequel chacun des radicaux est non substitué ou substitué ;
    Y est NR', S ou O, dans lequel R' représente hydrogène ou alkyle ;
    R représente aryle, hétérocyclylè, cycloalkyle, aryl-alkyle, hétérocyclyl-alkyle ou cycloalkyl-alkyle, dans lequel chacun des radicaux est non substitué ou substitué ; ou est COOR', COR' ou CONR'R", dans lequel R' et R", indépendamment les uns des autres, sont hydrogène ou alkyle, aryle, hétérocyclyle, cycloalkyle, aryl-allcyle, hétérocyclyl-alkyle ou cycloalkyl-alkyle, dans lesquels chacun des radicaux est non substitué ou substitué ; et
    Q est aryle, aryl-alkyle, hétérocyclyle, hétérocyclyl-alkyle, cycloalkyle ou cycloalkyl-alkyle, respectivement non substitué ou substitué ;
    ou un de ses sels pharmaceutiquement acceptables, pour la préparation d'une préparation pharmaceutique pour le traitement de maladies associées à une angiogenèse déréglée et/ou pour le traitement de tumeurs bénignes ou malignes.
  17. Procédé pour la préparation d'un composé de formule II illustré à la revendication 1, caractérisé en ce que
    (a) un composé de formule II
    Figure imgb0037

    dans laquelle X et R possèdent les significations données pour un composé de formule I à la revendication 1 et dans laquelle L représente un groupe partant, est réagi avec une amine, un phénol ou un thiol de formule III,

            Q-YH     (III)

    dans laquelle Q possèdent les significations données pour un composé de formule I et dans laquelle Y est NR', S ou O, dans lequel R' représente hydrogène ou alkyle ; dans laquelle, si nécessaire, les groupes fonctionnels présents dans un composé de formule II et/ou III, qui ne doivent pas prendre part à la réaction, sont présents sous forme protégée, et dans laquelle les groupes protecteurs présents sont clivés. et, si souhaité, un composé de formule I pouvant être obtenu est converti en un groupe différent de formule I ; un composé libre de formule I pouvant être obtenu est converti en un sel ; un sel d'un composé de formule I est converti en un autre sel ou en composé libre de formule I ; et/ou des mélanges isomériques de composés de formule I pouvant être obtenus sont séparés en des isomères individuels.
EP02740590A 2001-05-14 2002-05-13 Oxazolopyrimidines et furopyrimidines et utilisation dans des agents pharmaceutiques contre les tumeurs Expired - Lifetime EP1390371B1 (fr)

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KR20050091462A (ko) * 2004-03-12 2005-09-15 한국과학기술연구원 푸로피리미딘 화합물 및 이를 포함하는 ｄｄｒ2 티로신키나아제 활성 저해제
WO2005095419A1 (fr) * 2004-04-01 2005-10-13 Takeda Pharmaceutial Company Limited Dérivé de thiazolopyrimidine
JP5033119B2 (ja) 2005-04-25 2012-09-26 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング キナーゼ阻害剤としての新規アザ複素環化合物
DE102005061171A1 (de) 2005-12-21 2007-07-05 Bayer Healthcare Ag Neue, cyclisch substituierte Furopyrimidin-Derivate und ihre Verwendung
DE102005061170A1 (de) 2005-12-21 2007-07-05 Bayer Healthcare Ag Neue, acyclisch substituierte Furopyrimidin-Derivate und ihre Verwendung
AU2007261923B2 (en) * 2006-06-22 2013-10-31 Nippon Chemiphar Co., Ltd. Agent for overcoming resistance to anti-cancer agent
DE102007019690A1 (de) * 2007-04-26 2008-10-30 Bayer Healthcare Ag Verwendung von cyclisch substituierten Furopyrimidin-Derivaten zur Behandlung der pulmonalen arteriellen Hypertonie
DE102007019691A1 (de) * 2007-04-26 2008-10-30 Bayer Healthcare Ag Verwendung von acyclisch substituierten Furopyrimidin-Derivaten zur Behandlung der pulmonalen arteriellen Hypertonie
DE102007027800A1 (de) 2007-06-16 2008-12-18 Bayer Healthcare Ag Substituierte bicyclische Heteroaryl-Verbindungen und ihre Verwendung
DE102007027799A1 (de) 2007-06-16 2008-12-18 Bayer Healthcare Ag Substituierte Furopyrimidine und ihre Verwendung
EP2583720A1 (fr) * 2008-07-15 2013-04-24 Sanofi Oxazolopyrimidines en tant qu'agonistes du récepteur Edg.1
UY32240A (es) 2008-11-14 2010-06-30 Boeringer Ingelheim Kg Nuevas 2,4-diaminopirimidinas, sus sales farmacéuticamente aceptables, composiciones conteniéndolas y aplicaciones.
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US8580816B2 (en) * 2011-07-07 2013-11-12 Sanofi Carboxylic acid derivatives having an oxazolo[5,4-b]pyridine ring
US8907093B2 (en) * 2011-07-07 2014-12-09 Sanofi Carboxylic acid derivatives having an oxazolo[4,5-c]pyridine ring
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DK1390371T3 (da) 2006-06-19
ES2259707T3 (es) 2006-10-16
WO2002092603A1 (fr) 2002-11-21
CN100378107C (zh) 2008-04-02
CA2449188A1 (fr) 2002-11-21
ATE319718T1 (de) 2006-03-15
DE60209721D1 (de) 2006-05-04
DE60209721T2 (de) 2006-09-07
PT1390371E (pt) 2006-07-31
US7294633B2 (en) 2007-11-13
CN1509291A (zh) 2004-06-30
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